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Lactoferrin and its Role in Wound Healing pp 25–42Cite as

Role of Hyaluronan in Wound Healing

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Abstract

Hyaluronan is a negatively charged high molecular weight connective tissue glycosaminoglycan (GAG). As well as heparin sulfate proteoglycan, hyaluronan is a major polysaccharide found in extra cellular matrix (ECM). Hyaluronan is mainly synthesized by mesenchymal cells and extruded into ECM in coordination with synthesis. Hyaluronan molecules form a continuous but porous meshwork structure. This property of hyaluronan may contribute to the hydrated microenvironment at sites of synthesis. Together with passive functions such as space filling molecule, hyaluronan interacts with cell surface receptors, and regulates cell function by activating intracellular signaling pathway. Hyaluronan is taken up by cell surface receptors for intracellular degradation. The degradation occurs in stepwise fashion by distinct enzymes, hyaluronidase-1 (HYAL1) and HYAL2. Hyaluronan fragment has distinct functions that are not found in normal high molecular weight hyaluronan. High molecular weight hyaluronan acts as a component of intact ECM and tends to maintain signals that promote normal cellular functions whereas hyaluronan fragment tends to induce cellular differentiation, tissue morphogenesis or tissue defense in response to injury. Consequently, hyaluronan exerts beneficial effects on many steps of wound healing process such as inflammation, reepithelialization and resolution.

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References

  1. Laurent TC, Fraser JR (1992) Hyaluronan. FASEB J 6(7):2397–2404

    PubMed  CAS  Google Scholar 

  2. Toole BP (2000) Hyaluronan is not just a goo! J Clin Invest 106(3):335–336

    PubMed  CAS  Google Scholar 

  3. Stern R (2003) Devising a pathway for hyaluronan catabolism: are we there yet? Glycobiology 13(12):105R–115R

    PubMed  CAS  Google Scholar 

  4. Jiang D, Liang J, Noble PW (2011) Hyaluronan as an immune regulator in human diseases. Physiol Rev 91(1):221–264

    PubMed  CAS  Google Scholar 

  5. Holmes MW, Bayliss MT, Muir H (1988) Hyaluronic acid in human articular cartilage. Age-related changes in content and size. Biochem J 250(2):435–441

    PubMed  CAS  Google Scholar 

  6. Fraser JR, Laurent TC, Laurent UB (1997) Hyaluronan: its nature, distribution, functions and turnover. J Intern Med 242(1):27–33

    PubMed  CAS  Google Scholar 

  7. Cowman MK, Matsuoka S (2005) Experimental approaches to hyaluronan structure. Carbohydr Res 340(5):791–809

    PubMed  CAS  Google Scholar 

  8. Cleland RL (1970) Ionic polysaccharides. IV. Free-rotation dimensions for disaccharide polymers. Comparison with experiment for hyaluronic acid. Biopolymers 9(7):811–824

    PubMed  CAS  Google Scholar 

  9. Scott D, Coleman PJ, Mason RM, Levick JR (1998) Direct evidence for the partial reflection of hyaluronan molecules by the lining of rabbit knee joints during trans-synovial flow. J Physiol 508(Pt 2):619–623

    PubMed  CAS  Google Scholar 

  10. Toole BP (2004) Hyaluronan: from extracellular glue to pericellular cue. Nat Rev Cancer 4(7):528–539

    PubMed  CAS  Google Scholar 

  11. Stojkovic M, Kolle S, Peinl S, Stojkovic P et al (2002) Effects of high concentrations of hyaluronan in culture medium on development and survival rates of fresh and frozen-thawed bovine embryos produced in vitro. Reproduction 124(1):141–153

    PubMed  CAS  Google Scholar 

  12. Prehm P (1990) Release of hyaluronate from eukaryotic cells. Biochem J 267(1):185–189

    PubMed  CAS  Google Scholar 

  13. Watanabe K, Yamaguchi Y (1996) Molecular identification of a putative human hyaluronan synthase. J Biol Chem 271(38):22945–22948

    PubMed  CAS  Google Scholar 

  14. Pasonen-Seppanen S, Karvinen S, Torronen K, Hyttinen JM et al (2003) EGF upregulates, whereas TGF-beta downregulates, the hyaluronan synthases Has2 and Has3 in organotypic keratinocyte cultures: correlations with epidermal proliferation and differentiation. J Invest Dermatol 120(6):1038–1044

    PubMed  Google Scholar 

  15. Weigel PH, Hascall VC, Tammi M (1997) Hyaluronan synthases. J Biol Chem 272(22):13997–14000

    PubMed  CAS  Google Scholar 

  16. Itano N, Atsumi F, Sawai T, Yamada Y et al (2002) Abnormal accumulation of hyaluronan matrix diminishes contact inhibition of cell growth and promotes cell migration. Proc Natl Acad Sci USA 99(6):3609–3614

    PubMed  CAS  Google Scholar 

  17. Itano N, Sawai T, Yoshida M, Lenas P et al (1999) Three isoforms of mammalian hyaluronan synthases have distinct enzymatic properties. J Biol Chem 274(35):25085–25092

    PubMed  CAS  Google Scholar 

  18. Spicer AP, Seldin MF, Olsen AS, Brown N et al (1997) Chromosomal localization of the human and mouse hyaluronan synthase genes. Genomics 41(3):493–497

    PubMed  CAS  Google Scholar 

  19. Spicer AP, McDonald JA (1998) Characterization and molecular evolution of a vertebrate hyaluronan synthase gene family. J Biol Chem 273(4):1923–1932

    PubMed  CAS  Google Scholar 

  20. Tien JY, Spicer AP (2005) Three vertebrate hyaluronan synthases are expressed during mouse development in distinct spatial and temporal patterns. Dev Dyn 233(1):130–141

    PubMed  CAS  Google Scholar 

  21. Sugiyama Y, Shimada A, Sayo T, Sakai S et al (1998) Putative hyaluronan synthase mRNA are expressed in mouse skin and TGF-beta upregulates their expression in cultured human skin cells. J Invest Dermatol 110(2):116–121

    PubMed  CAS  Google Scholar 

  22. Sayo T, Sugiyama Y, Takahashi Y, Ozawa N et al (2002) Hyaluronan synthase 3 regulates hyaluronan synthesis in cultured human keratinocytes. J Invest Dermatol 118(1):43–48

    PubMed  CAS  Google Scholar 

  23. Camenisch TD, Spicer AP, Brehm-Gibson T, Biesterfeldt J et al (2000) Disruption of hyaluronan synthase-2 abrogates normal cardiac morphogenesis and hyaluronan-mediated transformation of epithelium to mesenchyme. J Clin Invest 106(3):349–360

    PubMed  CAS  Google Scholar 

  24. Li Y, Rahmanian M, Widstrom C, Lepperdinger G et al (2000) Irradiation-induced expression of hyaluronan (HA) synthase 2 and hyaluronidase 2 genes in rat lung tissue accompanies active turnover of HA and induction of types I and III collagen gene expression. Am J Respir Cell Mol Biol 23(3):411–418

    PubMed  CAS  Google Scholar 

  25. Tammi R, Pasonen-Seppanen S, Kolehmainen E, Tammi M (2005) Hyaluronan synthase induction and hyaluronan accumulation in mouse epidermis following skin injury. J Invest Dermatol 124(5):898–905

    PubMed  CAS  Google Scholar 

  26. Bai KJ, Spicer AP, Mascarenhas MM, Yu L et al (2005) The role of hyaluronan synthase 3 in ventilator-induced lung injury. Am J Respir Crit Care Med 172(1):92–98

    PubMed  Google Scholar 

  27. Suzuki M, Asplund T, Yamashita H, Heldin CH et al (1995) Stimulation of hyaluronan biosynthesis by platelet-derived growth factor-BB and transforming growth factor-beta 1 involves activation of protein kinase C. Biochem J 307(Pt 3):817–821

    PubMed  CAS  Google Scholar 

  28. Heldin P, Laurent TC, Heldin CH (1989) Effect of growth factors on hyaluronan synthesis in cultured human fibroblasts. Biochem J 258(3):919–922

    PubMed  CAS  Google Scholar 

  29. Li L, Asteriou T, Bernert B, Heldin CH et al (2007) Growth factor regulation of hyaluronan synthesis and degradation in human dermal fibroblasts: importance of hyaluronan for the mitogenic response of PDGF-BB. Biochem J 404(2):327–336

    PubMed  CAS  Google Scholar 

  30. Wilkinson TS, Potter-Perigo S, Tsoi C, Altman LC et al (2004) Pro- and anti-inflammatory factors cooperate to control hyaluronan synthesis in lung fibroblasts. Am J Respir Cell Mol Biol 31(1):92–99

    PubMed  CAS  Google Scholar 

  31. Pienimaki JP, Rilla K, Fulop C, Sironen RK et al (2001) Epidermal growth factor activates hyaluronan synthase 2 in epidermal keratinocytes and increases pericellular and intracellular hyaluronan. J Biol Chem 276(23):20428–20435

    PubMed  CAS  Google Scholar 

  32. Stuhlmeier KM, Pollaschek C (2004) Differential effect of transforming growth factor beta (TGF-beta) on the genes encoding hyaluronan synthases and utilization of the p38 MAPK pathway in TGF-beta-induced hyaluronan synthase 1 activation. J Biol Chem 279(10):8753–8760

    PubMed  CAS  Google Scholar 

  33. Jacobson A, Brinck J, Briskin MJ, Spicer AP et al (2000) Expression of human hyaluronan synthases in response to external stimuli. Biochem J 348(Pt 1):29–35

    PubMed  CAS  Google Scholar 

  34. Laurent UB, Dahl LB, Reed RK (1991) Catabolism of hyaluronan in rabbit skin takes place locally, in lymph nodes and liver. Exp Physiol 76(5):695–703

    PubMed  CAS  Google Scholar 

  35. Culty M, Nguyen HA, Underhill CB (1992) The hyaluronan receptor (CD44) participates in the uptake and degradation of hyaluronan. J Cell Biol 116(4):1055–1062

    PubMed  CAS  Google Scholar 

  36. Hua Q, Knudson CB, Knudson W (1993) Internalization of hyaluronan by chondrocytes occurs via receptor-mediated endocytosis. J Cell Sci 106(Pt 1):365–375

    PubMed  CAS  Google Scholar 

  37. Kaya G, Rodriguez I, Jorcano JL, Vassalli P et al (1997) Selective suppression of CD44 in keratinocytes of mice bearing an antisense CD44 transgene driven by a tissue-specific promoter disrupts hyaluronate metabolism in the skin and impairs keratinocyte proliferation. Genes Dev 11(8):996–1007

    PubMed  CAS  Google Scholar 

  38. Ponta H, Sherman L, Herrlich PA (2003) CD44: from adhesion molecules to signalling regulators. Nat Rev Mol Cell Biol 4(1):33–45

    PubMed  CAS  Google Scholar 

  39. Nandi A, Estess P, Siegelman MH (2000) Hyaluronan anchoring and regulation on the surface of vascular endothelial cells is mediated through the functionally active form of CD44. J Biol Chem 275(20):14939–14948

    PubMed  CAS  Google Scholar 

  40. Sherman L, Sleeman J, Herrlich P, Ponta H (1994) Hyaluronate receptors: key players in growth, differentiation, migration and tumor progression. Curr Opin Cell Biol 6(5):726–733

    PubMed  CAS  Google Scholar 

  41. Lesley J, Hyman R, Kincade PW (1993) CD44 and its interaction with extracellular matrix. Adv Immunol 54:271–335

    PubMed  CAS  Google Scholar 

  42. Svee K, White J, Vaillant P, Jessurun J et al (1996) Acute lung injury fibroblast migration and invasion of a fibrin matrix is mediated by CD44. J Clin Invest 98(8):1713–1727

    PubMed  CAS  Google Scholar 

  43. Peck D, Isacke CM (1996) CD44 phosphorylation regulates melanoma cell and fibroblast migration on, but not attachment to, a hyaluronan substratum. Curr Biol 6(7):884–890

    PubMed  CAS  Google Scholar 

  44. Legg JW, Lewis CA, Parsons M, Ng T et al (2002) A novel PKC-regulated mechanism controls CD44 ezrin association and directional cell motility. Nat Cell Biol 4(6):399–407

    PubMed  CAS  Google Scholar 

  45. Ito T, Williams JD, Fraser D, Phillips AO (2004) Hyaluronan attenuates transforming growth factor-beta1-mediated signaling in renal proximal tubular epithelial cells. Am J Pathol 164(6):1979–1988

    PubMed  CAS  Google Scholar 

  46. Ito T, Williams JD, Fraser DJ, Phillips AO (2004) Hyaluronan regulates transforming growth factor-beta1 receptor compartmentalization. J Biol Chem 279(24):25326–25332

    PubMed  CAS  Google Scholar 

  47. Peterson LF, Wang Y, Lo MC, Yan M et al (2007) The multi-functional cellular adhesion molecule CD44 is regulated by the 8;21 chromosomal translocation. Leukemia 21(9):2010–2019

    PubMed  CAS  Google Scholar 

  48. Alstergren P, Zhu B, Glogauer M, Mak TW et al (2004) Polarization and directed migration of murine neutrophils is dependent on cell surface expression of CD44. Cell Immunol 231(1–2):146–157

    PubMed  CAS  Google Scholar 

  49. Sconocchia G, Campagnano L, Adorno D, Iacona A et al (2001) CD44 ligation on peripheral blood polymorphonuclear cells induces interleukin-6 production. Blood 97(11):3621–3627

    PubMed  CAS  Google Scholar 

  50. Vivers S, Dransfield I, Hart SP (2002) Role of macrophage CD44 in the disposal of inflammatory cell corpses. Clin Sci (Lond) 103(5):441–449

    CAS  Google Scholar 

  51. Yang B, Zhang L, Turley EA (1993) Identification of two hyaluronan-binding domains in the hyaluronan receptor RHAMM. J Biol Chem 268(12):8617–8623

    PubMed  CAS  Google Scholar 

  52. Hardwick C, Hoare K, Owens R, Hohn HP et al (1992) Molecular cloning of a novel hyaluronan receptor that mediates tumor cell motility. J Cell Biol 117(6):1343–1350

    PubMed  CAS  Google Scholar 

  53. Turley EA, Austen L, Vandeligt K, Clary C (1991) Hyaluronan and a cell-associated hyaluronan binding protein regulate the locomotion of ras-transformed cells. J Cell Biol 112(5):1041–1047

    PubMed  CAS  Google Scholar 

  54. Tolg C, Poon R, Fodde R, Turley EA et al (2003) Genetic deletion of receptor for hyaluronan-mediated motility (Rhamm) attenuates the formation of aggressive fibromatosis (desmoid tumor). Oncogene 22(44):6873–6882

    PubMed  CAS  Google Scholar 

  55. Savani RC, Wang C, Yang B, Zhang S et al (1995) Migration of bovine aortic smooth muscle cells after wounding injury. The role of hyaluronan and RHAMM. J Clin Invest 95(3):1158–1168

    PubMed  CAS  Google Scholar 

  56. Gao F, Yang CX, Mo W, Liu YW et al (2008) Hyaluronan oligosaccharides are potential stimulators to angiogenesis via RHAMM mediated signal pathway in wound healing. Clin Invest Med 31(3):E106–116

    PubMed  CAS  Google Scholar 

  57. Hall CL, Yang B, Yang X, Zhang S et al (1995) Overexpression of the hyaluronan receptor RHAMM is transforming and is also required for H-ras transformation. Cell 82(1):19–26

    PubMed  CAS  Google Scholar 

  58. Hall CL, Wang C, Lange LA, Turley EA (1994) Hyaluronan and the hyaluronan receptor RHAMM promote focal adhesion turnover and transient tyrosine kinase activity. J Cell Biol 126(2):575–588

    PubMed  CAS  Google Scholar 

  59. Hamilton SR, Fard SF, Paiwand FF, Tolg C et al (2007) The hyaluronan receptors CD44 and Rhamm (CD168) form complexes with ERK1,2 that sustain high basal motility in breast cancer cells. J Biol Chem 282(22):16667–16680

    PubMed  CAS  Google Scholar 

  60. Jiang D, Liang J, Fan J, Yu S et al (2005) Regulation of lung injury and repair by Toll-like receptors and hyaluronan. Nat Med 11(11):1173–1179

    PubMed  CAS  Google Scholar 

  61. Taylor KR, Yamasaki K, Radek KA, Di Nardo A et al (2007) Recognition of hyaluronan released in sterile injury involves a unique receptor complex dependent on Toll-like receptor 4, CD44, and MD-2. J Biol Chem 282(25):18265–18275

    PubMed  CAS  Google Scholar 

  62. Termeer C, Benedix F, Sleeman J, Fieber C et al (2002) Oligosaccharides of Hyaluronan activate dendritic cells via toll-like receptor 4. J Exp Med 195(1):99–111

    PubMed  CAS  Google Scholar 

  63. Jackson DG (2009) Immunological functions of hyaluronan and its receptors in the lymphatics. Immunol Rev 230(1):216–231

    PubMed  CAS  Google Scholar 

  64. Gale NW, Prevo R, Espinosa J, Ferguson DJ et al (2007) Normal lymphatic development and function in mice deficient for the lymphatic hyaluronan receptor LYVE-1. Mol Cell Biol 27(2):595–604

    PubMed  CAS  Google Scholar 

  65. Csoka AB, Frost GI, Wong T, Stern R (1997) Purification and microsequencing of hyaluronidase isozymes from human urine. FEBS Lett 417(3):307–310

    PubMed  CAS  Google Scholar 

  66. Csoka AB, Scherer SW, Stern R (1999) Expression analysis of six paralogous human hyaluronidase genes clustered on chromosomes 3p21 and 7q31. Genomics 60(3):356–361

    PubMed  CAS  Google Scholar 

  67. Rai SK, Duh FM, Vigdorovich V, Danilkovitch-Miagkova A et al (2001) Candidate tumor suppressor HYAL2 is a glycosylphosphatidylinositol (GPI)-anchored cell-surface receptor for jaagsiekte sheep retrovirus, the envelope protein of which mediates oncogenic transformation. Proc Natl Acad Sci USA 98(8):4443–4448

    PubMed  CAS  Google Scholar 

  68. Mullegger J, Lepperdinger G (2002) Degradation of hyaluronan by a Hyal2-type hyaluronidase affects pattern formation of vitelline vessels during embryogenesis of Xenopus laevis. Mech Dev 111(1–2):25–35

    PubMed  CAS  Google Scholar 

  69. Lepperdinger G, Strobl B, Kreil G (1998) HYAL2, a human gene expressed in many cells, encodes a lysosomal hyaluronidase with a novel type of specificity. J Biol Chem 273(35):22466–22470

    PubMed  CAS  Google Scholar 

  70. Jadin L, Wu X, Ding H, Frost GI et al (2008) Skeletal and hematological anomalies in HYAL2-deficient mice: a second type of mucopolysaccharidosis IX? FASEB J 22(12):4316–4326

    PubMed  CAS  Google Scholar 

  71. Knudson W, Chow G, Knudson CB (2002) CD44-mediated uptake and degradation of hyaluronan. Matrix Biol 21(1):15–23

    PubMed  CAS  Google Scholar 

  72. Monzon ME, Manzanares D, Schmid N, Casalino-Matsuda SM et al (2008) Hyaluronidase expression and activity is regulated by pro-inflammatory cytokines in human airway epithelial cells. Am J Respir Cell Mol Biol 39(3):289–295

    PubMed  CAS  Google Scholar 

  73. Csoka AB, Frost GI, Stern R (2001) The six hyaluronidase-like genes in the human and mouse genomes. Matrix Biol 20(8):499–508

    PubMed  CAS  Google Scholar 

  74. Atmuri V, Martin DC, Hemming R, Gutsol A et al (2008) Hyaluronidase 3 (HYAL3) knockout mice do not display evidence of hyaluronan accumulation. Matrix Biol 27(8):653–660

    PubMed  CAS  Google Scholar 

  75. Kaneiwa T, Mizumoto S, Sugahara K, Yamada S (2010) Identification of human hyaluronidase-4 as a novel chondroitin sulfate hydrolase that preferentially cleaves the galactosaminidic linkage in the trisulfated tetrasaccharide sequence. Glycobiology 20(3):300–309

    PubMed  CAS  Google Scholar 

  76. Gmachl M, Sagan S, Ketter S, Kreil G (1993) The human sperm protein PH-20 has hyaluronidase activity. FEBS Lett 336(3):545–548

    PubMed  CAS  Google Scholar 

  77. Horton MR, McKee CM, Bao C, Liao F et al (1998) Hyaluronan fragments synergize with interferon-gamma to induce the C-X-C chemokines mig and interferon-inducible protein-10 in mouse macrophages. J Biol Chem 273(52):35088–35094

    PubMed  CAS  Google Scholar 

  78. McKee CM, Penno MB, Cowman M, Burdick MD (1996) Hyaluronan (HA) fragments induce chemokine gene expression in alveolar macrophages. The role of HA size and CD44. J Clin Invest 98(10):2403–2413

    PubMed  CAS  Google Scholar 

  79. Noble PW, McKee CM, Cowman M, Shin HS (1996) Hyaluronan fragments activate an NF-kappa B/I-kappa B alpha autoregulatory loop in murine macrophages. J Exp Med 183(5):2373–2378

    PubMed  CAS  Google Scholar 

  80. McKee CM, Lowenstein CJ, Horton MR, Wu J et al (1997) Hyaluronan fragments induce nitric-oxide synthase in murine macrophages through a nuclear factor kappaB-dependent mechanism. J Biol Chem 272(12):8013–8018

    PubMed  CAS  Google Scholar 

  81. Stuhlmeier KM (2006) Aspects of the biology of hyaluronan, a largely neglected but extremely versatile molecule. Wien Med Wochenschr 156(21–22):563–568

    PubMed  Google Scholar 

  82. Noble PW (2002) Hyaluronan and its catabolic products in tissue injury and repair. Matrix Biol 21(1):25–29

    PubMed  CAS  Google Scholar 

  83. Mascarenhas MM, Day RM, Ochoa CD, Choi WI et al (2004) Low molecular weight hyaluronan from stretched lung enhances interleukin-8 expression. Am J Respir Cell Mol Biol 30(1):51–60

    PubMed  CAS  Google Scholar 

  84. Tesar BM, Jiang D, Liang J, Palmer SM et al (2006) The role of hyaluronan degradation products as innate alloimmune agonists. Am J Transplant 6(11):2622–2635

    PubMed  CAS  Google Scholar 

  85. Mummert ME, Mohamadzadeh M, Mummert DI, Mizumoto N et al (2000) Development of a peptide inhibitor of hyaluronan-mediated leukocyte trafficking. J Exp Med 192(6):769–779

    PubMed  CAS  Google Scholar 

  86. Kuppusamy UR, Khoo HE, Das NP (1990) Structure-activity studies of flavonoids as inhibitors of hyaluronidase. Biochem Pharmacol 40(2):397–401

    PubMed  CAS  Google Scholar 

  87. Montesano R, Kumar S, Orci L, Pepper MS (1996) Synergistic effect of hyaluronan oligosaccharides and vascular endothelial growth factor on angiogenesis in vitro. Lab Invest 75(2):249–262

    PubMed  CAS  Google Scholar 

  88. Gao F, Cao M, Yang C, He Y et al (2006) Preparation and characterization of hyaluronan oligosaccharides for angiogenesis study. J Biomed Mater Res B Appl Biomater 78(2):385–392

    PubMed  Google Scholar 

  89. Savani RC, Cao G, Pooler PM, Zaman A et al (2001) Differential involvement of the hyaluronan (HA) receptors CD44 and receptor for HA-mediated motility in endothelial cell function and angiogenesis. J Biol Chem 276(39):36770–36778

    PubMed  CAS  Google Scholar 

  90. Slevin M, Kumar S, Gaffney J (2002) Angiogenic oligosaccharides of hyaluronan induce multiple signaling pathways affecting vascular endothelial cell mitogenic and wound healing responses. J Biol Chem 277(43):41046–41059

    PubMed  CAS  Google Scholar 

  91. Termeer CC, Hennies J, Voith U, Ahrens T et al (2000) Oligosaccharides of hyaluronan are potent activators of dendritic cells. J Immunol 165(4):1863–1870

    PubMed  CAS  Google Scholar 

  92. Termeer C, Sleeman JP, Simon JC (2003) Hyaluronan–magic glue for the regulation of the immune response? Trends Immunol 24(3):112–114

    PubMed  CAS  Google Scholar 

  93. Ghatak S, Misra S, Toole BP (2002) Hyaluronan oligosaccharides inhibit anchorage-independent growth of tumor cells by suppressing the phosphoinositide 3-kinase/Akt cell survival pathway. J Biol Chem 277(41):38013–38020

    PubMed  CAS  Google Scholar 

  94. Xu H, Ito T, Tawada A, Maeda H et al (2002) Effect of hyaluronan oligosaccharides on the expression of heat shock protein 72. J Biol Chem 277(19):17308–17314

    PubMed  CAS  Google Scholar 

  95. West DC, Hampson IN, Arnold F, Kumar S (1985) Angiogenesis induced by degradation products of hyaluronic acid. Science 228(4705):1324–1326

    PubMed  CAS  Google Scholar 

  96. Sironen RK, Tammi M, Tammi R, Auvinen PK et al (2011) Hyaluronan in human malignancies. Exp Cell Res 317(4):383–391

    PubMed  CAS  Google Scholar 

  97. Toole BP, Biswas C, Gross J (1979) Hyaluronate and invasiveness of the rabbit V2 carcinoma. Proc Natl Acad Sci USA 76(12):6299–6303

    PubMed  CAS  Google Scholar 

  98. Turley EA, Bowman P, Kytryk MA (1985) Effects of hyaluronate and hyaluronate binding proteins on cell motile and contact behaviour. J Cell Sci 78:133–145

    PubMed  CAS  Google Scholar 

  99. Toole BP, Wight TN, Tammi MI (2002) Hyaluronan-cell interactions in cancer and vascular disease. J Biol Chem 277(7):4593–4596

    PubMed  CAS  Google Scholar 

  100. Auvinen P, Tammi R, Parkkinen J, Tammi M et al (2000) Hyaluronan in peritumoral stroma and malignant cells associates with breast cancer spreading and predicts survival. Am J Pathol 156(2):529–536

    PubMed  CAS  Google Scholar 

  101. Zhang L, Underhill CB, Chen L (1995) Hyaluronan on the surface of tumor cells is correlated with metastatic behavior. Cancer Res 55(2):428–433

    PubMed  CAS  Google Scholar 

  102. Kosaki R, Watanabe K, Yamaguchi Y (1999) Overproduction of hyaluronan by expression of the hyaluronan synthase Has2 enhances anchorage-independent growth and tumorigenicity. Cancer Res 59(5):1141–1145

    PubMed  CAS  Google Scholar 

  103. Koyama H, Kobayashi N, Harada M, Takeoka M et al (2008) Significance of tumor-associated stroma in promotion of intratumoral lymphangiogenesis: pivotal role of a hyaluronan-rich tumor microenvironment. Am J Pathol 172(1):179–193

    PubMed  CAS  Google Scholar 

  104. Koyama H, Hibi T, Isogai Z, Yoneda M et al (2007) Hyperproduction of hyaluronan in neu-induced mammary tumor accelerates angiogenesis through stromal cell recruitment: possible involvement of versican/PG-M. Am J Pathol 170(3):1086–1099

    PubMed  CAS  Google Scholar 

  105. Zoltan-Jones A, Huang L, Ghatak S, Toole BP (2003) Elevated hyaluronan production induces mesenchymal and transformed properties in epithelial cells. J Biol Chem 278(46):45801–45810

    PubMed  CAS  Google Scholar 

  106. Liu N, Gao F, Han Z, Xu X et al (2001) Hyaluronan synthase 3 overexpression promotes the growth of TSU prostate cancer cells. Cancer Res 61(13):5207–5214

    PubMed  CAS  Google Scholar 

  107. Yu Q, Stamenkovic I (2000) Cell surface-localized matrix metalloproteinase-9 proteolytically activates TGF-beta and promotes tumor invasion and angiogenesis. Genes Dev 14(2):163–176

    PubMed  Google Scholar 

  108. Tammi R, Saamanen AM, Maibach HI, Tammi M (1991) Degradation of newly synthesized high molecular mass hyaluronan in the epidermal and dermal compartments of human skin in organ culture. J Invest Dermatol 97(1):126–130

    PubMed  CAS  Google Scholar 

  109. Turley E, Moore D (1984) Hyaluronate binding proteins also bind to fibronectin, laminin and collagen. Biochem Biophys Res Commun 121(3):808–814

    PubMed  CAS  Google Scholar 

  110. Isemura M, Yosizawa Z, Koide T, Ono T (1982) Interaction of fibronectin and its proteolytic fragments with hyaluronic acid. J Biochem 91(2):731–734

    PubMed  CAS  Google Scholar 

  111. Baccarani-Contri M, Vincenzi D, Cicchetti F, Mori G et al (1990) Immunocytochemical localization of proteoglycans within normal elastin fibers. Eur J Cell Biol 53(2):305–312

    PubMed  CAS  Google Scholar 

  112. Tammi R, MacCallum D, Hascall VC, Pienimaki JP et al (1998) Hyaluronan bound to CD44 on keratinocytes is displaced by hyaluronan decasaccharides and not hexasaccharides. J Biol Chem 273(44):28878–28888

    PubMed  CAS  Google Scholar 

  113. Tammi R, Tammi M (1991) Correlations between hyaluronan and epidermal proliferation as studied by [3H]glucosamine and [3H]thymidine incorporations and staining of hyaluronan on mitotic keratinocytes. Exp Cell Res 195(2):524–527

    PubMed  CAS  Google Scholar 

  114. Oksala O, Salo T, Tammi R, Hakkinen L et al (1995) Expression of proteoglycans and hyaluronan during wound healing. J Histochem Cytochem 43(2):125–135

    PubMed  CAS  Google Scholar 

  115. Foschi D, Castoldi L, Radaelli E, Abelli P et al (1990) Hyaluronic acid prevents oxygen free-radical damage to granulation tissue: a study in rats. Int J Tissue React 12(6):333–339

    PubMed  CAS  Google Scholar 

  116. King SR, Hickerson WL, Proctor KG (1991) Beneficial actions of exogenous hyaluronic acid on wound healing. Surgery 109(1):76–84

    PubMed  CAS  Google Scholar 

  117. Luke HJ, Prehm P (1999) Synthesis and shedding of hyaluronan from plasma membranes of human fibroblasts and metastatic and non-metastatic melanoma cells. Biochem J 343(Pt 1):71–75

    PubMed  CAS  Google Scholar 

  118. Wisniewski HG, Naime D, Hua JC, Vilcek J et al (1996) TSG-6, a glycoprotein associated with arthritis, and its ligand hyaluronan exert opposite effects in a murine model of inflammation. Pflugers Arch 431(6 Suppl 2):R225–226

    PubMed  CAS  Google Scholar 

  119. Kobayashi H, Terao T (1997) Hyaluronic acid-specific regulation of cytokines by human uterine fibroblasts. Am J Physiol 273(4 Pt 1):C1151–1159

    PubMed  CAS  Google Scholar 

  120. Chen WY, Abatangelo G (1999) Functions of hyaluronan in wound repair. Wound Repair Regen 7(2):79–89

    PubMed  CAS  Google Scholar 

  121. Frost SJ, Weigel PH (1990) Binding of hyaluronic acid to mammalian fibrinogens. Biochim Biophys Acta 1034(1):39–45

    PubMed  CAS  Google Scholar 

  122. Weigel PH, Fuller GM, LeBoeuf RD (1986) A model for the role of hyaluronic acid and fibrin in the early events during the inflammatory response and wound healing. J Theor Biol 119(2):219–234

    PubMed  CAS  Google Scholar 

  123. Knudson CB, Knudson W (1993) Hyaluronan-binding proteins in development, tissue homeostasis, and disease. FASEB J 7(13):1233–1241

    PubMed  CAS  Google Scholar 

  124. Toole BP (2001) Hyaluronan in morphogenesis. Semin Cell Dev Biol 12(2):79–87

    PubMed  CAS  Google Scholar 

  125. Jenkins RH, Thomas GJ, Williams JD, Steadman R (2004) Myofibroblastic differentiation leads to hyaluronan accumulation through reduced hyaluronan turnover. J Biol Chem 279(40):41453–41460

    PubMed  CAS  Google Scholar 

  126. Desmouliere A, Guyot C, Gabbiani G (2004) The stroma reaction myofibroblast: a key player in the control of tumor cell behavior. Int J Dev Biol 48(5–6):509–517

    PubMed  CAS  Google Scholar 

  127. Gabbiani G (2003) The myofibroblast in wound healing and fibrocontractive diseases. J Pathol 200(4):500–503

    PubMed  CAS  Google Scholar 

  128. Meran S, Thomas D, Stephens P, Martin J et al (2007) Involvement of hyaluronan in regulation of fibroblast phenotype. J Biol Chem 282(35):25687–25697

    PubMed  CAS  Google Scholar 

  129. Evanko SP, Angello JC, Wight TN (1999) Formation of hyaluronan- and versican-rich pericellular matrix is required for proliferation and migration of vascular smooth muscle cells. Arterioscler Thromb Vasc Biol 19(4):1004–1013

    PubMed  CAS  Google Scholar 

  130. Knudson CB, Toole BP (1985) Fluorescent morphological probe for hyaluronate. J Cell Biol 100(5):1753–1758

    PubMed  CAS  Google Scholar 

  131. Knudson CB, Knudson W (1990) Similar epithelial-stromal interactions in the regulation of hyaluronate production during limb morphogenesis and tumor invasion. Cancer Lett 52(2):113–122

    PubMed  CAS  Google Scholar 

  132. Knudson CB, Munaim SI, Toole BP (1995) Ectodermal stimulation of the production of hyaluronan-dependent pericellular matrix by embryonic limb mesodermal cells. Dev Dyn 204(2):186–191

    PubMed  CAS  Google Scholar 

  133. Webber J, Meran S, Steadman R, Phillips A (2009) Hyaluronan orchestrates transforming growth factor-beta1-dependent maintenance of myofibroblast phenotype. J Biol Chem 284(14):9083–9092

    PubMed  CAS  Google Scholar 

  134. Clark RA, Lin F, Greiling D, An J et al (2004) Fibroblast invasive migration into fibronectin/fibrin gels requires a previously uncharacterized dermatan sulfate-CD44 proteoglycan. J Invest Dermatol 122(2):266–277

    PubMed  CAS  Google Scholar 

  135. Acharya PS, Majumdar S, Jacob M, Hayden J et al (2008) Fibroblast migration is mediated by CD44-dependent TGF beta activation. J Cell Sci 121(Pt 9):1393–1402

    PubMed  CAS  Google Scholar 

  136. Huebener P, Abou-Khamis T, Zymek P, Bujak M et al (2008) CD44 is critically involved in infarct healing by regulating the inflammatory and fibrotic response. J Immunol 180(4):2625–2633

    PubMed  CAS  Google Scholar 

  137. Tolg C, Hamilton SR, Nakrieko KA, Kooshesh F et al (2006) Rhamm−/− fibroblasts are defective in CD44-mediated ERK1,2 motogenic signaling, leading to defective skin wound repair. J Cell Biol 175(6):1017–1028

    PubMed  CAS  Google Scholar 

  138. Tammi RH, Tammi MI (2009) Hyaluronan accumulation in wounded epidermis: a mediator of keratinocyte activation. J Invest Dermatol 129(8):1858–1860

    PubMed  CAS  Google Scholar 

  139. Sato H, Takahashi T, Ide H, Fukushima T et al (1988) Antioxidant activity of synovial fluid, hyaluronic acid, and two subcomponents of hyaluronic acid. Synovial fluid scavenging effect is enhanced in rheumatoid arthritis patients. Arthritis Rheum 31(1):63–71

    PubMed  CAS  Google Scholar 

  140. Bates EJ, Harper GS, Lowther DA, Preston BN (1984) Effect of oxygen-derived reactive species on cartilage proteoglycan-hyaluronate aggregates. Biochem Int 8(5):629–637

    PubMed  CAS  Google Scholar 

  141. Deguine V, Menasche M, Ferrari P, Fraisse L et al (1998) Free radical depolymerization of hyaluronan by Maillard reaction products: role in liquefaction of aging vitreous. Int J Biol Macromol 22(1):17–22

    PubMed  CAS  Google Scholar 

  142. Monzon ME, Fregien N, Schmid N, Falcon NS et al (2010) Reactive oxygen species and hyaluronidase 2 regulate airway epithelial hyaluronan fragmentation. J Biol Chem 285(34):26126–26134

    PubMed  CAS  Google Scholar 

  143. Gao F, Koenitzer JR, Tobolewski JM, Jiang D et al (2008) Extracellular superoxide dismutase inhibits inflammation by preventing oxidative fragmentation of hyaluronan. J Biol Chem 283(10):6058–6066

    PubMed  CAS  Google Scholar 

  144. Martin P (1997) Wound healing–aiming for perfect skin regeneration. Science 276(5309):75–81

    PubMed  CAS  Google Scholar 

  145. Beanes SR, Dang C, Soo C, Ting K (2003) Skin repair and scar formation: the central role of TGF-beta. Expert Rev Mol Med 5(8):1–22

    PubMed  Google Scholar 

  146. Singer AJ, Clark RA (1999) Cutaneous wound healing. N Engl J Med 341(10):738–746

    PubMed  CAS  Google Scholar 

  147. Lorenz HP, Whitby DJ, Longaker MT, Adzick NS (1993) Fetal wound healing. The ontogeny of scar formation in the non-human primate. Ann Surg 217(4):391–396

    PubMed  CAS  Google Scholar 

  148. Longaker MT, Chiu ES, Adzick NS, Stern M et al (1991) Studies in fetal wound healing. V. A prolonged presence of hyaluronic acid characterizes fetal wound fluid. Ann Surg 213(4):292–296

    PubMed  CAS  Google Scholar 

  149. Chen WY, Grant ME, Schor AM, Schor SL (1989) Differences between adult and foetal fibroblasts in the regulation of hyaluronate synthesis: correlation with migratory activity. J Cell Sci 94(Pt 3):577–584

    PubMed  CAS  Google Scholar 

  150. David-Raoudi M, Tranchepain F, Deschrevel B, Vincent JC et al (2008) Differential effects of hyaluronan and its fragments on fibroblasts: relation to wound healing. Wound Repair Regen 16(2):274–287

    PubMed  Google Scholar 

  151. Smith LT, Holbrook KA, Madri JA (1986) Collagen types I, III, and V in human embryonic and fetal skin. Am J Anat 175(4):507–521

    PubMed  CAS  Google Scholar 

  152. Merkel JR, DiPaolo BR, Hallock GG, Rice DC (1988) Type I and type III collagen content of healing wounds in fetal and adult rats. Proc Soc Exp Biol Med 187(4):493–497

    PubMed  CAS  Google Scholar 

  153. Volk SW, Wang Y, Mauldin EA, Liechty KW (2011) Diminished Type III Collagen Promotes Myofibroblast Differentiation and Increases Scar Deposition in Cutaneous Wound Healing. Cells Tissues Organs 194(1):25–37

    PubMed  CAS  Google Scholar 

  154. Karvinen S, Pasonen-Seppanen S, Hyttinen JM, Pienimaki JP et al (2003) Keratinocyte growth factor stimulates migration and hyaluronan synthesis in the epidermis by activation of keratinocyte hyaluronan synthases 2 and 3. J Biol Chem 278(49):49495–49504

    PubMed  CAS  Google Scholar 

  155. Pasonen-Seppanen SM, Maytin EV, Torronen KJ, Hyttinen JM et al (2008) All-trans retinoic acid-induced hyaluronan production and hyperplasia are partly mediated by EGFR signaling in epidermal keratinocytes. J Invest Dermatol 128(4):797–807

    PubMed  CAS  Google Scholar 

  156. Rilla K, Pasonen-Seppanen S, Rieppo J, Tammi M et al (2004) The hyaluronan synthesis inhibitor 4-methylumbelliferone prevents keratinocyte activation and epidermal hyperproliferation induced by epidermal growth factor. J Invest Dermatol 123(4):708–714

    PubMed  CAS  Google Scholar 

  157. Passi A, Sadeghi P, Kawamura H, Anand S et al (2004) Hyaluronan suppresses epidermal differentiation in organotypic cultures of rat keratinocytes. Exp Cell Res 296(2):123–134

    PubMed  CAS  Google Scholar 

  158. Tammi R, Ripellino JA, Margolis RU, Maibach HI et al (1989) Hyaluronate accumulation in human epidermis treated with retinoic acid in skin organ culture. J Invest Dermatol 92(3):326–332

    PubMed  CAS  Google Scholar 

  159. Agren UM, Tammi M, Tammi R (1995) Hydrocortisone regulation of hyaluronan metabolism in human skin organ culture. J Cell Physiol 164(2):240–248

    PubMed  CAS  Google Scholar 

  160. Larjava H, Saarni H, Tammi M, Penttinen R et al (1980) Cortisol decreases the synthesis of hyaluronic acid by human aortic smooth muscle cells in culture. Atherosclerosis 35(2):135–143

    PubMed  CAS  Google Scholar 

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  1. Functional Bio-molecules Research Team, National Institute of Livestock and Grassland Science, Ikenodai 2, 305-0901, Tsukuba, Ibaraki, Japan

    Yoshiharu Takayama

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Takayama, Y. (2012). Role of Hyaluronan in Wound Healing. In: Lactoferrin and its Role in Wound Healing. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-2467-9_2

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